Calacanis's biggest success to date is Weblogs, Inc., which was sold to AOL in 2005. Before forming Weblogs, Inc., Calacanis was founder and CEO of Rising Tide Studios, a media company that published print and online publications. During the dot-com boom, Calacanis was active in New York's Silicon Alley community, and in 1996 began producing the Silicon Alley Reporter. Originally a 16-page photocopied newsletter, it eventually expanded into a 300-page magazine, with a sister publication called the Digital Coast Reporter for the West Coast. Calacanis's socializing earned him a nickname as the "yearbook editor" of the Silicon Alley community.[10] The company also organized conferences in New York, Los Angeles, and San Francisco focused on the Internet, web, and New Media. With the end of the Dot-com bubble, Silicon Alley Reporter failed, and the company was sold out of bankruptcy to a private equity firm.[11]

Eight months into his tenure with AOL, Calacanis was offered the position of General Manager of the new Netscape website. Calacanis copied the model pioneered by Digg, Del.icio.us, and Furl and added an editorial layer to the system, like Slashdot. The project occupied the front page of Netscape. Calacanis started by hiring a team of eight "anchors" to follow up users' top stories. He then hired some of the top users of social bookmarking sites like Digg, Reddit, Newsvine and Flickr to go to Netscape as Netscape Navigators,[15] which prompted a public debate with Kevin Rose, founder of Digg, most notably during a live taping of the video podcast Diggnation.[16]

On November 16, 2006, TechCrunch reported that Calacanis had resigned from his position as CEO of Weblogs, Inc. and General Manager of Netscape.[17] Calacanis later confirmed this with a post on his blog.[18][19]

Calacanis founded Mahalo.com, a "human-powered search engine",[23] which launched in alpha test in May 2007. During a speech about the site at the Gnomedex conference in August 2007, Calacanis got into a public confrontation with Dave Winer that led to Winer's resignation from the panel of experts for the TechCrunch20 conference organized by Calacanis. Winer interrupted Calacanis' speech during the event, calling it "conference spam" and igniting a war of words on their blogs. "I'm not interested in having someone berate me like this," Calacanis wrote on his blog.[24]

Mahalo ("thank you" in Hawaiian), raised $20 million in venture capital from investors including Sequoia Capital, News Corp, CBS, Mark Cuban, and Elon Musk. The company's motto: "We're here to help." At its peak, it had 14.1 million global (7.4 million US) unique monthly visitors.[25] Mahalo shut down in 2014.

In 2009, Calacanis founded the Open Angel Forum, an event that connects early stage startups with angel investors. The forum was the culmination of a series of public comments by Calacanis questioning the ethics of pay-to-pitch angel forums.[26] Calacanis believes startups shouldn't have to pay to pitch angel investors.[27]

Calacanis raised a $10 million fund to for his own venture investment firm to invest in startups that emerged from the Launch conference.[28][29] Limited partners in the fund include David Sacks.[30] Following the success of the Launch conference,[31] Mr. Calacanis aims to get closer and more involved in the new ventures that emerged from that conference.[32] The approach of investment is around $25,000 to $100,000 in five to 10 startups per year.[33][34]

Calacanis is the founder of ThisWeekIn.com,[35] a podcast network, and the host of the live streamed "This Week In Startups" show, one of the featured podcasts.[36] In 2010, the company raised a seed round of about $300,000 from Matt Coffin, Sky Dayton, and Calacanis himself.

On December 14, 2012, Calacanis announced that he would be shutting down his podcast network ThisWeekIn.com.[37] The shut down of the company did not mean the end of its three most popular shows, which are still in live production: This Week In Startups, This Week In Web Design and Kevin Pollak’s Chat Show.

This Week in Startups (also called TWiSt) is a show hosted by Jason that has published more than 500 episodes. Typically, TWiSt produces two episodes a week, one on Tuesday and one on Friday. Tuesday shows generally feature founders, CEOs, entrepreneurs, angel investors and venture capitalists talking about startups, entrepreneurship and the Web industry in general.[38] Friday shows feature a round table format show[39] that usually runs over an hour of conversation about the web startup industry with a rotating panel of commentators. The show has gained popularity amongst the startup community, averaging 100,000 regular listeners[citation needed], and routinely attracts well-known speaker-guests.[40][41] Calacanis and a continuous fresh group of speaker-guests[42][43] that are well known within the industry, sometimes experts, share their stories and thoughts on the Web industry, their ventures andcompanies and trends.[44][45] including the live broadcast[46][47] on its main site[48] as well as iTunes/Audio & iTunes/Video.

Calacanis announced the creation of the Launch Festival to spotlight unannounced start-ups. The first Festival was held on February 23 and 24, 2011, and featured 140 startups. A number of companies received funding at the event and the winners included Room 77 and GreenGoose. LAUNCH Festivals are held each year in the spring.

During a dinner meeting between Calacanis and Elon Musk, Musk mentioned that the second Space X rocket had exploded and that Tesla Motors had only two weeks of funding left. Calacanis enquired about any good news; Musk confided in him that a new car (Tesla Model S) was close to development and might cost $50,000. Upon arriving home, Calacanis wrote out two $50,000 cheques to Tesla with a note stating "E looks like a great car. I will take two". Two years later the cheques were cashed and Calacanis took delivery of two Tesla Model S cars. The first has the serial number 00001 and the second 00073.[50]

During a speech about his company Mahalo at Gnomedex in 2007, Calacanis was heckled from the audience. The heckler was Dave Winer. Winer accused Calacanis of "spamming the audience" with a Mahalo pitch.[52] Winer later reiterated his disdain for Calacanis, stating "It's all about Jason and his investors making money. Why should I care about that?"[53]

Calacanis was involved in a 2010 Internet hoax involving his Twitter postings regarding the introduction of the Apple iPad. In his tweets, he claimed to have a "reviewer's copy" of an iPad device describing in great detail the features of such device. The device in question was not in his possession nor did it exist. It was explained to have been an attempt by Calacanis to expose the hysteria regarding Apple product launches. The hoax also called into question the fact checking and verification processes of the mainstream media who published the hoax story as true.[54][55]